Two Church lab vets, a secretive institute and an Israeli billionaire hunt for drugs in the guts of wild animals
Over the last four years, Neta Raab and Ido Bachelet have received hundreds of padded cardboard boxes containing frozen poop from wild animals on five different continents.
The packages came regularly to their lab outside Tel Aviv, sent from a squad of zoologists and specialized Israeli army veterans who tracked enough animals to fill a Rudyard Kipling novel, rushing to collect vulture and rhino and frog samples within an hour of extrusion. Raab and Bachelet carefully opened the boxes, removing the samples from plastic-wrapped tubes and then using specialized magnetic beads to fish out the bacterial DNA inside for sequencing.
The result of that effort appeared Thursday in Science, where Raab, Bachelet and prominent Israeli computational biologist Eran Segal published what amounts to the largest database ever assembled of the microbiome, or gut bacteria, inside different members of the animal kingdom. Sampling nearly 200 animals, they documented 5,000 genomes across over 1,200 different bacterial species, most of which had never been seen before.
Jack GilbertIt’s a major scientific achievement, outside experts say, one that will allow the growing number of researchers studying the microbiome inside particular animals, including humans, to fit their findings into a broader context. But for Raab and Bachelet, two veterans of the George Church Lab, it’s also a vast trove of genetic information that could be mined for new drugs on a long list of diseases.
They’ve launched a company, Wild Biotech, to begin turning the genes they found into therapies for immunological, inflammatory and gastrointestinal conditions. The idea is that these bacteria have, over millions of years, evolved proteins to carry out a wide range of unique functions for their hosts. Tapping and engineering those proteins could help correct problems in humans.
“This resource really does create a platform — a springboard if you will — to accelerate research, to help us leverage the microbiome in treating disease, improving health, restoring ecosystems,” says Jack Gilbert, a microbial ecologist at UC San Diego who is not involved in the research or the company.
Timewise, he adds, bacteria have a leg up on any medicinal chemist in a drug lab. “If you think about it, nature has been experimenting with variants in microbial chemistry for billions of years,” he says. “That’s a lot of experimentation — way more than any human endeavor could hope to achieve.”
Dan LittmanWild Biotech joins the long list of companies that have raised billions to leverage scientists’ growing understanding of the human microbiome into new drugs for cancer or infectious disease. Those efforts, though, have largely focused on giving people tablets containing strains of living bacteria from humans, relying on the confluence of hundreds of different genes to restore a healthy immune system.
In trying to tap animal microbiomes and isolate individual proteins, Raab and Bachelet will have to show a deeper understanding of the bacteria and the function of the genes they uncovered. They say they have that technology and they’ve received an eminent backer in Israeli billionaire Marius Nacht, but so far, it remains unpublished and unproven.
“My guess is that there’s gonna be a lot of valuable medicinal information in there,” says Dan Littman, a professor of molecular immunology at NYU and co-founder of the microbiome biotech Vedanta. “But it’s going to take an enormous amount of work to go from here to the next step of making a valuable product.”
A hyena creating a microbiome sample in Uganda. Researchers will collect it within the hour (Gal Zanir)
Click on the image to see the full-sized version
A secretive Israeli institute with some bird questions
Wild Biotech grew out of work Raab, Bachelet and their third cofounder, Doron Levin, conducted at a small institute in Rehovot, Israel called Augmanity. Bachelet did his postdoc at the Church lab, where he started making a name in a field of nanotechnology called DNA origami, and he says he founded Augmanity after leaving academia to back ambitious scientific projects. But he offered no other details, including what other work they do or how many people work there.
“We’re a very stealthy organization,” Bachelet says, pointing me to a single-page website that was offline at the time. “There’s no sign on the building, there’s no sign on the door.”
Raab, a former student and now Wild’s CEO, joined Augmanity after her own stint at the Church lab, hoping to help build Israel’s biotech scene.
The microbiome project arose out of several ideas they had about birds: Israel is a landing spot for billions of birds migrating between Africa and Europe — could they sample their droppings and warn countries of the pathogenic bacteria they carry? They also wondered about the microbiomes in vultures and other scavengers. These animals eat rotting flesh, so they need to evade or withstand the toxins in the bacteria that grow on corpses. Did they use their own microbiomes to do so?
Soon, they were asking about all sorts of different animals and how they survived conditions humans never encounter. “So the idea was born from many different small questions,” Raab says. “But at some point, we kind of had an epiphany.”
Raab worked with experts from the Israeli safari and IDF specialists to track animals in Hungary, Uganda, the Falkland Islands, Madagascar, Australia and Israel. They used drones to follow animals and teamed with guides and rangers to track them by foot and vehicle. They put up nets to trap and band birds. They boarded inflatable boats to trail whales off the Falkland Islands, skimming samples on the water’s surface.
Along with the fecal sample, trackers also logged details about the individual animal and location. Other researchers have looked at a wide range of captive animals, but Raab wanted wild animals, pointing to research that captivity can change or even cripple an animal’s microbiome.
“It changes their capacity to return to nature,” she says. “And we really wanted to look for the specific features that enable them to really survive in the hostile and harsh environments.”
To analyze the samples after they arrived in Israel, Bachelet and Raab reached out to Segal, a pioneer in computational genetics who sometimes worked on the human microbiome. The two labs broke the DNA they extracted — a tangle of strands from all the various microbes in a given fecal sample called a “metagenome” — into small pieces that can be read by a sequencer. The sequencer spits out an incomprehensible jumble of fragments from hundreds or thousands of different bacteria. But by looking for places where the different fragments overlap, the researchers can stitch complete genomes back together.
They can then tag individual genes by looking for recognizable patterns. Every gene, for example, starts and ends with string of letters called a “start” and “stop” codon.
“A metagenome is like an incomplete jigsaw puzzle thrown on the floor,” says Gilbert, the UCSD researcher. “What they’ve done is take those puzzle pieces and start to piece them together.”
Surprising insights
The work immediately brought surprises. David Zeevi, a PhD student at Segal’s lab who worked on the metagenome analysis, says bacteria that live on land and in the sea generally have similar genomes. So he was shocked by how much the microbiomes could vary between species and how many new genes appeared.
“They have such a huge diversity, huge potential of new microbial genes,” says Zeevi, who is now an independent fellow at Rockefeller about to launch his own microbiome lab at the Weizmann Institute. “What are the selective pressures, in terms of evolution, that led to something like this?”
For Bachelet and Raab, though, the big question is whether they can translate the database into drugs. They began linking the genes they found to traits in the paper, showing for example differences between carnivores and herbivores that might give meat-eaters enhanced abilities to combat toxic bacteria.
As a proof-of-concept, they synthesized one protein found in griffon vultures’ microbiome they believed helped it combat the deadly synapse-cutting poison botulinum toxin A. It turned out that the protein actually sped up the toxin’s effect — part of what the researchers believe is a cascade of enzymes griffons use to clear it.
Botulinum toxin A is also the key ingredient in AbbVie billion-dollar Botox. Perhaps, Bachelet says, you can use the griffon protein to create a fast-acting Botox, or “Super-Botox.” “That’s already a market,” he says.
Naama Geva ZatorskyNaama Geva-Zatorsky, who runs a systems biology lab at the Technion, agreed the toxin provided a good test case, adding that she’d now like to see larger work on collecting, studying and freezing animal microbiome samples, as researchers have done with human microbiomes.
“This is a purely beautiful study!” she said in an email. “Translating to medicine is totally feasible.”
Not everyone is convinced, though. David Berry, a partner at Flagship who played a pivotal role in founding the microbiome biotechs Seres Therapeutics, Evelo Biosciences and Indigo Agriculture, says their work brought major insights into an under-explored area. In the past, though, he says researchers have struggled to isolate individual genes that give a particular gut bacterium its impact.
David BerryOftentimes, scientists would see two strains of the same species, one that has a profound effect on its host and one that doesn’t. But when they tried to compare the two genomes to find the difference, they would find millions of differences — on the same scale that separates human and bananas, say, or humans and fungi — making it impossible to single out a protein that could be therapeutic.
Still, he adds, sometimes they found chemicals produced by the microbes that were pivotal.
“I wouldn’t rule out the potential that there’s something deeply important and deeply insightful in the data,” he says. “But I think there’s a whole bunch of steps that have to be taken to turn this into something that can produce drugs.”
A wild future
Bachelet and Raab are now working on those steps. So far they’re keeping most details about the company under wraps. They say they have a far larger database than the one they published in Science and an AI-assisted software that can link the individual genes they found to potential impact particular disorders.
They’re focusing, Bachelet says, on proteins and functions you can’t find in the human microbiome and that might offer new routes of administration or the ability to radically alter the immune system. With billionaire Nacht’s backing, they’ve built a 9-person-team without having to rely on traditional VC funding.
The company has a couple lead candidates from the initial analysis and they’ll work on expanding the platform and refining the software for at least the next year, before they potentially need more funding. In the meantime, they’ve frozen all their old samples should they need to be tested again or if they want to try to culture individual strains living inside. It’s a one-of-a-kind resource for the future.
“We’re heads down,” Raab says. “It’s early, still.”
